Inflammatory diseases of the skin, such as psoriasis and atopic dermatitis, afflict greater than 5% of the population. Currently, the treatment of these disorders typically involves the use of topical steroids. However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.
Phospholipase A.sub.2 (PLA.sub.2) is the common name for phosphatide 2-acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
PLA.sub.2 enzymes exist as secreted forms (MW.about.12,000-15,000) and cytosolic forms (MW.about.85,000). The cytosolic or cPLA.sub.2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
Inappropriate activation of the cytosolic PLA.sub.2 enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke 1996, 27, 527-535), Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke, 1996, 3, 51-63 and see also U.S. Pat, No. 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation 1994,3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham et al., American Journal of Physiology 1996, 270; Cell Physiology 39:C1037-C1050) and macrophage activation (Balsinde et al, Journal of Biological Chemistry 1996,271,6758-6765).
Selective inhibitors of the cPLA.sub.2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A.sub.2 inhibitors, but few selective inhibitors for the cPLA.sub.2 enzymes are available. The present inventors had as their goal the synthesis of novel compounds which would be selective and potent inhibitors of the cPLA.sub.2 enzymes. As used herein, the term "selective inhibitors of the cPLA.sub.2 enzymes" means that the inhibitors inhibit the cPLA.sub.2 enzymes with a potency 20-fold or greater than they inhibit the lower molecular weight synovial PLA.sub.2 enzymes.
Biochemistry 32: 5935-5940, 1993, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula ##STR2##
Bioorganic Med. Chem. Lett. 5: 519-522, 1995, discloses selective cPLA.sub.2 inhibitors of the formula ##STR3##
where R is either H or OH.
Japanese published patent application JP09268153A (Derwent No. 97-554679/51) discloses cPLA.sub.2 inhibitors of the formula RCOCF.sub.3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or antiallergic drugs.
Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula ##STR4##
wherein
A represents a C.sub.4 -C.sub.10 alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of --CH.dbd.CH--B,--O--B,--S--B, and --NH--B, or radicals of formula --CH.sub.2 --X,
wherein
B represents a non-aromatic C.sub.3 -C.sub.8 carbocycle, a C.sub.3 -C.sub.8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
X is a member selected from the group consisting of a halogen atom, --S--aryl,--S--heterocycle, and --PO.sub.3 R.sub.2 wherein each R is independently selected from the group consisting of a hydrogen atom and C.sub.1 -C.sub.3 alkyl;
R.sup.1 and R.sup.2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: --(CH.sub.2).sub.q --A' wherein q is an integer of 2 to 4, and A' is a member selected from the group consisting of a hydroxyl group, a group represented by the formula: ##STR5##
wherein R.sup.5 and R.sup.6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: ##STR6##
wherein R.sup.7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula: ##STR7##
wherein s is an integer of 2 to 5; or
R.sup.1 and R.sup.2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula: ##STR8##
wherein g and h are each an integer of 1 to 4, and B' stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or
R.sup.1 and R.sup.2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R.sup.1 and R.sup.2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
R.sup.3 represents a hydrogen atom, a lower alkyl group, or a C.sub.3 -C.sub.8 cycloalkyl group;
R.sup.4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom;
n is an integer of 1 to 4, provided that when n is 2, the two R.sup.4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A.sub.2 activity, particularly cPLA.sub.2.
Drugs 1998, Vol. 1, No. 1, pp. 49-50 discloses cPLA.sub.2 inhibitors of the type
##STR9## R.sub.1 R.sub.2 X CH.sub.3 (1) (1) CH.sub.3 (CH.sub.2).sub.9 -- CH.sub.3 (CH.sub.2).sub.9 -- Ph(CH.sub.2).sub.5 O O O S ##STR10## (1) CH.sub.3 (CH.sub.2).sub.9 -- SO.sub.2
U.S. Pat. No. 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA.sub.2 enzymes, but it is not indicated whether these compounds are selective for the cytosolic enzymes or even whether they inhibit the cytosolic enzymes. These compounds have the generic formula ##STR11##
wherein:
R.sup.1 is selected from
(a) hydrogen,
(b)--C.sub.1-6 alkyl, and
(c)--C.sub.1-6 alkyl-phenyl;
or wherein R.sup.1 and R.sup.5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms; R.sup.2 and R.sup.3 are each independently selected from
(a) hydrogen,
(b) C.sub.1-6 alkyl, and
(c) C.sub.1-6 alkyl-phenyl,
or wherein two R.sup.2 or two R.sup.3 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R.sup.5 is as defined above or is selected from
(a) hydrogen
(b)--C.sub.1-6 alkyl,
(c)--C.sub.1-6 alkyl-phenylC.sub.1-6 alkyl,
(d) --OH,
(e) --O--C.sub.1-6 alkyl, or
(f) --C.sub.1-6 alkyl-phenylC.sub.1-6 alkyl;
R.sup.6 is selected from
(a) hydrogen
(b) --C.sub.1-6 alkyl,
(c) --C.sub.1-6 alkyl-phenyl, wherein the phenyl is optionally substituted with C.sub.1-2 alkyl;
(d) --OH,
(e) --O--C.sub.1-6 alkyl, or
(f) --O--C.sub.1-6 alkyl-phenyl, wherein the phenyl is optionally substituted with C.sub.1-2 alkyl;
or wherein two R.sup.6 are joined to form O.dbd. or are joined together such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5,6, 7 or 8 atoms;
R.sup.8, R.sup.9 and R.sup.14 are each independently selected from
(a) H,
(b) --C.sub.1-6 alkyl,
(c) halo
(d) --CN
(e) --OH
(f) --OC.sub.1-6 alkyl,
(g) --OC.sub.1-6 alkyl-phenyl,
(h) --SR.sup.11
(i) S(O)R.sup.11, or
(j) S(O).sub.2 R.sup.11 ;
R.sup.10, R.sup.15, R.sup.16 and R.sup.17 are each independently selected from
(a) hydrogen,
(b) --C.sub.1-6 alkyl, and
(c) --C.sub.1-6, alkyl-phenyl;
R.sup.11 is selected from
(a) --C.sub.1-6 alkyl,
(b) --C.sub.2-6 alkenyl,
(c) --CF.sub.3,
(d) --phenyl(R.sup.12).sub.2, or
(e) --C.sub.2-6 alkenyl-phenyl(R.sup.12).sub.2,
R.sup.12 is
(a) hydrogen,
(b) --C.sub.1-6 alkyl,
(c) Cl, F, I or Br;
R.sup.13 is perfluoroC.sub.1-6 alkyl;
A and B are each independently
(a) covalent bond,
(b) O,
(c) S,
(d) S(O), or
(e) S(O).sub.2 ;
Q is selected from
(a) --CH(OH)R.sup.13,
(b) --COR.sup.13,
(c) --COR.sup.16, or
(d) --C.sub.1-4 alkylCOCOOR.sup.17 ;
X.sup.1 is selected from
(a) --O--,
(b) --S--,
(c) --S(O)--,
(d) --S(O).sub.2 ;
Z is
(a) H, or
(b) --phenyl--(R.sup.14).sub.3,
m is 0,1,2,3 or 4;
n is 2,3,4,5,6 or 7; and
r and s are each independently 0,1,2,3,4,5,6,7 or 8.